Antagonizing L-type Ca2+ Channel Reduces Development of Abnormal Involuntary Movement in the Rat Model of L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia
(2009) In Biological Psychiatry 65(6). p.518-526- Abstract
- Background: Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experimental models of DA depletion. This loss of connectivity is triggered by a dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Here we address the possible implication of DA denervation-induced spine pruning in the development of L-DOPA-induced dyskinesia. Methods: The L-type Ca2+ antagonist, isradipine was subcutaneously delivered to rats at the doses of .05, .1, or .2 mg/kg/day, for 4 weeks, starting the day after a unilateral... (More)
- Background: Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experimental models of DA depletion. This loss of connectivity is triggered by a dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Here we address the possible implication of DA denervation-induced spine pruning in the development of L-DOPA-induced dyskinesia. Methods: The L-type Ca2+ antagonist, isradipine was subcutaneously delivered to rats at the doses of .05, .1, or .2 mg/kg/day, for 4 weeks, starting the day after a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion. Fourteen days later, L-DOPA treatment was initiated. Results: Isradipine-treated animals displayed a dose-dependent reduction in L-DOPA-induced rotational behavior and abnormal involuntary movements. Dendritic spine counting at electron microscopy level showed that isradipine (.2 mg/kg/day) prevented the 6-OHDA-induced spine loss and normalized preproenkephalin-A messenger RNA expression. Involuntary movements were not reduced when isradipine treatment was started concomitantly with L-DOPA. Conclusions: These results indicate that isradipine, at a therapeutically relevant dose, might represent a treatment option for preventing L-DOPA-induced dyskinesia in PD. (Less)
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https://lup.lub.lu.se/record/1370791
- author
- organization
- publishing date
- 2009
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- medium spiny neurons, isradipine, Parkinson's, disease, Electron microscopy
- in
- Biological Psychiatry
- volume
- 65
- issue
- 6
- pages
- 518 - 526
- publisher
- Elsevier
- external identifiers
-
- wos:000263895900010
- scopus:60349126440
- ISSN
- 0006-3223
- DOI
- 10.1016/j.biopsych.2008.09.008
- language
- English
- LU publication?
- yes
- id
- bad59941-7931-41e2-9800-36bc0fbc027a (old id 1370791)
- date added to LUP
- 2016-04-01 12:03:44
- date last changed
- 2024-06-19 10:17:28
@article{bad59941-7931-41e2-9800-36bc0fbc027a, abstract = {{Background: Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experimental models of DA depletion. This loss of connectivity is triggered by a dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Here we address the possible implication of DA denervation-induced spine pruning in the development of L-DOPA-induced dyskinesia. Methods: The L-type Ca2+ antagonist, isradipine was subcutaneously delivered to rats at the doses of .05, .1, or .2 mg/kg/day, for 4 weeks, starting the day after a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion. Fourteen days later, L-DOPA treatment was initiated. Results: Isradipine-treated animals displayed a dose-dependent reduction in L-DOPA-induced rotational behavior and abnormal involuntary movements. Dendritic spine counting at electron microscopy level showed that isradipine (.2 mg/kg/day) prevented the 6-OHDA-induced spine loss and normalized preproenkephalin-A messenger RNA expression. Involuntary movements were not reduced when isradipine treatment was started concomitantly with L-DOPA. Conclusions: These results indicate that isradipine, at a therapeutically relevant dose, might represent a treatment option for preventing L-DOPA-induced dyskinesia in PD.}}, author = {{Schuster, Stefan and Doudnikoff, Evelyne and Rylander, Daniella and Berthet, Amandine and Aubert, Incarnation and Ittrich, Carina and Bloch, Bertrand and Cenci, M. Angela and Surmeier, D. James and Hengerer, Bastian and Bezard, Erwan}}, issn = {{0006-3223}}, keywords = {{medium spiny neurons; isradipine; Parkinson's; disease; Electron microscopy}}, language = {{eng}}, number = {{6}}, pages = {{518--526}}, publisher = {{Elsevier}}, series = {{Biological Psychiatry}}, title = {{Antagonizing L-type Ca2+ Channel Reduces Development of Abnormal Involuntary Movement in the Rat Model of L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia}}, url = {{http://dx.doi.org/10.1016/j.biopsych.2008.09.008}}, doi = {{10.1016/j.biopsych.2008.09.008}}, volume = {{65}}, year = {{2009}}, }